Endocrine Abstracts (2008) 16 P336

G12/13-dependent growth of small cell lung cancer cells in vitro and in vivo

Thomas Büch, Marius Grzelinski, Olaf Pinkenburg, Maike Gold, Achim Aigner & Thomas Gudermann

Philipps University, Marburg, Germany.

The malignant phenotype of small cell lung cancer (SCLC) cells critically relies on the autocrine stimulation of G12/13- and Gq/11-coupled neuropeptide receptors. By this means, G12/13- and Gq/11-dependent signalling pathways are constitutively activated in these cells. While Gq/11-dependent signalling has been shown to promote proliferation of SCLC cells, the role of signalling pathways via G12/13 is still elusive. Thus, we employed shRNA-mediated down-regulation of Gα12, Gα13, or both, in human SCLC cell lines. The use of a lentiviral expression system rather than non-viral transfection resulted in robust, specific, and stable knockdown of both target proteins. This decrease in Gα12 or Gα13 levels markedly reduced proliferation in SCLC cell lines in normal culture medium as well as colony formation in semi-solid medium. However, double targeting of both Gα12 and Gα13 did not exert a synergistic anti-proliferative effect in vitro. In a subcutaneous tumor xenograft mouse model, the downregulation of Gα12 or Gα13 resulted in decreased tumor growth, which was due to reduced tumor cell proliferation. More importantly, double knock-down of Gα12 and Gα13 completely abolished tumorigenicity in mice. Thus, intact G12/13 signalling is a prerequisite for proliferation of SCLC cells in vitro and tumorigenicity in vivo.

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